US10040048B1 - Automated modular system and method for production of biopolymers - Google Patents

Automated modular system and method for production of biopolymers Download PDF

Info

Publication number
US10040048B1
US10040048B1 US14/866,091 US201514866091A US10040048B1 US 10040048 B1 US10040048 B1 US 10040048B1 US 201514866091 A US201514866091 A US 201514866091A US 10040048 B1 US10040048 B1 US 10040048B1
Authority
US
United States
Prior art keywords
system
production
oligonucleotide
automated
plurality
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US14/866,091
Inventor
Paul Dabrowski
Michael Dabrowski
Fabian Gerlinghaus
Alex Pesch
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Synthego Corp
Original Assignee
Synthego Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to US201462055419P priority Critical
Application filed by Synthego Corp filed Critical Synthego Corp
Priority to US14/866,091 priority patent/US10040048B1/en
Assigned to SYNTHEGO CORPORATION reassignment SYNTHEGO CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DABROWSKI, MICHAEL, DABROWSKI, PAUL, GERLINGHAUS, FABIAN, PESCH, ALEX
Application granted granted Critical
Publication of US10040048B1 publication Critical patent/US10040048B1/en
Application status is Active legal-status Critical
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J19/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J19/0046Sequential or parallel reactions, e.g. for the synthesis of polypeptides or polynucleotides; Apparatus and devices for combinatorial chemistry or for making molecular arrays
    • GPHYSICS
    • G05CONTROLLING; REGULATING
    • G05BCONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
    • G05B19/00Programme-control systems
    • G05B19/02Programme-control systems electric
    • G05B19/418Total factory control, i.e. centrally controlling a plurality of machines, e.g. direct or distributed numerical control [DNC], flexible manufacturing systems [FMS], integrated manufacturing systems [IMS], computer integrated manufacturing [CIM]
    • G05B19/41815Total factory control, i.e. centrally controlling a plurality of machines, e.g. direct or distributed numerical control [DNC], flexible manufacturing systems [FMS], integrated manufacturing systems [IMS], computer integrated manufacturing [CIM] characterised by the cooperation between machine tools, manipulators and conveyor or other workpiece supply system, workcell
    • G05B19/4182Total factory control, i.e. centrally controlling a plurality of machines, e.g. direct or distributed numerical control [DNC], flexible manufacturing systems [FMS], integrated manufacturing systems [IMS], computer integrated manufacturing [CIM] characterised by the cooperation between machine tools, manipulators and conveyor or other workpiece supply system, workcell manipulators and conveyor only
    • GPHYSICS
    • G05CONTROLLING; REGULATING
    • G05BCONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
    • G05B19/00Programme-control systems
    • G05B19/02Programme-control systems electric
    • G05B19/418Total factory control, i.e. centrally controlling a plurality of machines, e.g. direct or distributed numerical control [DNC], flexible manufacturing systems [FMS], integrated manufacturing systems [IMS], computer integrated manufacturing [CIM]
    • G05B19/4189Total factory control, i.e. centrally controlling a plurality of machines, e.g. direct or distributed numerical control [DNC], flexible manufacturing systems [FMS], integrated manufacturing systems [IMS], computer integrated manufacturing [CIM] characterised by the transport system
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00279Features relating to reactor vessels
    • B01J2219/00306Reactor vessels in a multiple arrangement
    • B01J2219/00313Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315Microtiter plates
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00277Apparatus
    • B01J2219/00279Features relating to reactor vessels
    • B01J2219/00306Reactor vessels in a multiple arrangement
    • B01J2219/00313Reactor vessels in a multiple arrangement the reactor vessels being formed by arrays of wells in blocks
    • B01J2219/00315Microtiter plates
    • B01J2219/00317Microwell devices, i.e. having large numbers of wells
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068Means for controlling the apparatus of the process
    • B01J2219/00686Automatic
    • B01J2219/00691Automatic using robots
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068Means for controlling the apparatus of the process
    • B01J2219/00693Means for quality control
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/0068Means for controlling the apparatus of the process
    • B01J2219/00702Processes involving means for analysing and characterising the products
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00718Type of compounds synthesised
    • B01J2219/0072Organic compounds
    • B01J2219/00722Nucleotides
    • BPERFORMING OPERATIONS; TRANSPORTING
    • B01PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01JCHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J2219/00Chemical, physical or physico-chemical processes in general; Their relevant apparatus
    • B01J2219/00274Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
    • B01J2219/00759Purification of compounds synthesised
    • GPHYSICS
    • G05CONTROLLING; REGULATING
    • G05BCONTROL OR REGULATING SYSTEMS IN GENERAL; FUNCTIONAL ELEMENTS OF SUCH SYSTEMS; MONITORING OR TESTING ARRANGEMENTS FOR SUCH SYSTEMS OR ELEMENTS
    • G05B2219/00Program-control systems
    • G05B2219/30Nc systems
    • G05B2219/45Nc applications
    • G05B2219/45092Analysing or chemical synthesis robot, moving samples from station to station
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P90/00Enabling technologies with a potential contribution to greenhouse gas [GHG] emissions mitigation
    • Y02P90/02Total factory control, e.g. smart factories, flexible manufacturing systems [FMS] or integrated manufacturing systems [IMS]
    • Y02P90/04Total factory control, e.g. smart factories, flexible manufacturing systems [FMS] or integrated manufacturing systems [IMS] characterised by the assembly processes
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P90/00Enabling technologies with a potential contribution to greenhouse gas [GHG] emissions mitigation
    • Y02P90/02Total factory control, e.g. smart factories, flexible manufacturing systems [FMS] or integrated manufacturing systems [IMS]
    • Y02P90/08Total factory control, e.g. smart factories, flexible manufacturing systems [FMS] or integrated manufacturing systems [IMS] characterised by the cooperation between machine tools, manipulators or work piece supply systems
    • Y02P90/083Manipulators cooperating with conveyors
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02PCLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P90/00Enabling technologies with a potential contribution to greenhouse gas [GHG] emissions mitigation
    • Y02P90/02Total factory control, e.g. smart factories, flexible manufacturing systems [FMS] or integrated manufacturing systems [IMS]
    • Y02P90/22Total factory control, e.g. smart factories, flexible manufacturing systems [FMS] or integrated manufacturing systems [IMS] characterised by quality surveillance of production
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10STECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S901/00Robots
    • Y10S901/02Arm motion controller

Abstract

The present invention provides an automated modular system and method for production of biopolymers including DNA and RNA. The system and method automates the complete production process for biopolymers. Modular equipment is provided for performing production steps with the individual modules arrange in a linear array. Each module includes a control system and can be rack mounted. One side of the array of modules provides connections for power, gas, vacuum and reagents and is accessible to technicians. On the other side of the array of modules a robotic transport system is provided for transporting materials between module interfaces. The elimination of the requirement for human intervention at multiple steps in the production process significantly decreases the costs of biopolymer production and reduces unnecessary complexity and sources of quality variation.

Description

CLAIM OF PRIORITY

This application claims priority to U.S. Provisional Patent Application No. 62/055,419, filed Sep. 25, 2014 entitled “AUTOMATED MODULAR SYSTEM AND METHOD FOR PRODUCTION OF BIOPOLYMERS” which application is incorporated herein by reference.

BACKGROUND OF THE INVENTION

Automated systems for the synthesis of DNA or RNA are available. However a complete process for the production of DNA or RNA requires a complex sequence of biochemical processes in addition to the synthesis step. These processes include, for example, preparation of reaction vessels, synthesis of oligonucleotides, cleavage of oligonucleotides from the synthesis support, elution of oligonucleotides, oligonucleotide purification, quantization and quality control of oligonucleotides, re-plating of oligonucleotides, dry down of loaded plates, packaging, and labeling. Although separate equipment is available for performing the individual steps, the full production process is typically labor intensive because it requires skilled technicians to operate the individual pieces of equipment and transport materials between the individual pieces of equipment. The requirement for human intervention at multiple steps in the production process significantly increases the costs of DNA and RNA production and introduces unnecessary complexity and sources of quality variation and error.

SUMMARY OF THE INVENTION

In view of the disadvantages of the state of the art, applicants have developed an automated modular system and method for production of DNA, RNA, modified nucleic acids, aptamers, peptides, and other biological polymers (hereinafter collectively referred to as biopolymers). In an embodiment, the system and method automates the complete production process for DNA and RNA including, for example, preparation of reaction vessels, synthesis of oligonucleotides, cleavage of oligonucleotides from the synthesis support, elution of oligonucleotides, oligonucleotide purification, quantization and quality control of oligonucleotides, re-plating of oligonucleotides, dry down of loaded plates, packaging, and labeling. Modular equipment is provided for performing these steps with the individual modules arranged in an array. Each module includes control systems and can be rack mounted. The rear side of the array of modules provides connections for power, gas, vacuum and reagents and is accessible to technicians. The front side of the array of modules provides mechanical interfaces for access by a robotic transport system which provides for automatic transportation of materials between the modules. The automated production system avoids labor intensive steps requiring skilled technicians to operate the individual pieces of equipment and transport materials between the individual pieces of equipment. The elimination of the requirement for human intervention at multiple steps in the production process significantly decreases the costs of DNA/RNA production and reduces unnecessary complexity and sources of quality variation and error.

The present invention provides an automated production system including a production control system for scheduling and controlling production in an automated production process and a plurality of equipment modules for processing materials under control of the production control system, wherein each equipment module comprises on a front side a mechanical interface for receiving materials and transmitting processed materials, and, on a rear side, an interface for connecting power, network, and any required fluids, and reagents. The plurality of equipment modules is arranged and secured in a linear array such that the mechanical interfaces are accessible from a front side of the linear array and all the interfaces are accessible from a rear side of the linear array. A robotic transport system positioned adjacent the front side of the modular equipment array includes a plurality of robot arms adapted to move materials and processed materials between the mechanical interfaces of the plurality of equipment modules under the control of the production control system whereby the automated production system avoids labor intensive steps requiring skilled technicians to operate the plurality of equipment modules and transport materials between the plurality of equipment modules thereby decreasing the cost of production, and reducing unnecessary complexity and sources of quality variation and error. In various embodiments, the automated production system may be configured to operate a biopolymer production process wherein the production process is one of a DNA synthesis process, an RNA synthesis process, an oligonucleotide synthesis process, an aptamer synthesis process, a peptide synthesis process, and a polymer synthesis process.

In an embodiment, the automated production system also provides for continuous quality control of input reagents and materials and output biopolymer products thereby providing for closed loop software control at the system, instrument and channel levels in which the system, instruments, and/or channels may be tuned or calibrated to enhance performance in response to the collected quality control data relevant to the system, instrument or channels. The quality control data can be continuously analyzed to determine tuning and or calibration that is required and transmit instructions to the instruments of the automated production system 100.

In a particular embodiment, the automated production system is configured for production of oligonucleotides. In the particular embodiment the plurality of equipment modules include an oligonucleotide synthesis module, an oligonucleotide purification module, an oligonucleotide quantization module; an oligonucleotide quality control module, an oligonucleotide re-plating module, a centrifuge module for oligonucleotide dry down and a packaging and labeling module. The automated production system is capable of automatically producing oligonucleotides under control of the production control system and without human intervention during the normal course of operation. Human intervention is only required for maintenance and for replacement of certain consumable parts and reagents.

Thus, the present invention provides an automated modular system and method for production of biopolymers. Although the particular automated production system described in the detailed description below is directed to the production of DNA and RNA, the modular system may be readily adapted by substitution of various components to the production of other biopolymers where it is necessary or desirable to produce a large number of different compounds in an automated and efficient manner or conduct analysis or experimentation in an automated and efficient manner. Other objects, features and advantages of the invention will be apparent from the drawings and detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and further features, advantages and benefits of the present invention will be apparent upon consideration of the present description taken in conjunction with the accompanying drawings.

FIG. 1 shows a complete automated biopolymer production system according to an embodiment of the present invention.

FIGS. 2A and 2B show an example of an equipment module for use in the automated biopolymer production system of FIG. 1 according to an embodiment of the present invention.

FIGS. 3A and 3B show aspects of a modular equipment array for use in the automated biopolymer production system of FIG. 1 according to an embodiment of the present invention.

FIGS. 3C-3E illustrate a supply system designed to facilitate connection of required utilities according to an embodiment of the present invention.

FIGS. 4A-4C show aspects of a robotic transport system for moving materials between equipment of the modular equipment array of FIGS. 3A and 3B according to an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The following description is of the best modes presently contemplated for practicing various embodiments of the present invention. The description is not to be taken in a limiting sense but is made merely for the purpose of describing the general principles of the invention. The scope of the invention should be ascertained with reference to the claims. In the description of the invention that follows, like numerals or reference designators will be used to refer to like parts or elements throughout. In addition, the first digit of a reference number identifies the set of drawings in which the reference number first appears.

Automated DNA/RNA Production Process

FIG. 1 shows an overview of an automated production system 100 according to an embodiment of the present invention. The automated production system 100 may be tailored to provide particular biochemical synthesis products and services. In the example shown in FIG. 1, automated production system 100 is tailored for the manufacture of DNA and RNA oligonucleotide products. The automated production system 100 includes a complete production process including, but not limited to, preparation of reaction vessels, synthesis of oligonucleotides, cleavage of oligonucleotides from the synthesis support, elution of oligonucleotides, oligonucleotide purification, quantization and quality control of oligonucleotides, re-plating of oligonucleotides, dry down of loaded plates, packaging and labeling. The production process requires the coordinated use of a variety of pieces of equipment and the automated transport of material between the equipment.

As described below, the equipment of automated production system 100 is organized as modules which are provided in a two dimensional array. The modules can be added and removed to the array. Connections to the equipment are facilitated by a technician accessible interface on the rear surface of each module while the front surface of each module has an automatic mechanical interface for receiving materials from and returning materials to a robotic transport system for automated transport of materials and products.

In general terms, customers 190 interact with customer interface 102. Customer interface 102 can include a website, Email and/or other communication mechanisms whereby customers can submit information including orders for e.g. DNA/RNA, billing information, and the like and receive information including order status, order results and the like. Orders for DNA/RNA include quantities and sequences of oligonucleotides to be prepared and details of any modified nucleotides/labels. The sequences, quantities and other details are provided to a production control system 110 which oversees the oligonucleotide production process. Preferably the customer interface 102 provides a high degree of automation such that little human intervention/human customer service is required to extract the information from customer communications necessary to drive the automated production process 100. After production, completed product is shipped to customer 190 from shipping interface 104. Additional order information about an order (such as identification of oligonucleotides and quantity/quality data) is communicated to customer 190 via customer interface 102.

Production control system 110 drives automated production system 100. Production control system 110 receives DNA/RNA production information from customer interface 102 and uses the information to determine what DNA/RNA to make and in what quantities. Production control system 110 provides instructions to and monitors each of the subsystems and processes in automated production system 100. Production control system 110 also monitors and tracks materials moving through automated production system 100 such that production control system maintains a record at all times as to which products are present in which vessels from the beginning of synthesis through to packaging and labeling of the final product. This eliminates the need for labelling intermediate products and eliminates the possibility of confusing or mislabeling intermediate products that can occur where technicians are required to move intermediate products between different stations of a production process which is not fully automated.

The automated production system 100 also provides for continuous quality control (as described below) of input reagents and materials and output biopolymer products such as DNA and RNA. The quality control data collected allows production control system 110 to provide for closed loop software control at the system, instrument and channel levels in which the system, instruments, and/or channels may be tuned or calibrated to enhance performance in response to the collected quality control data relevant to the system, instrument or channels. The quality control data can be continuously analyzed by the production control system 110 to determine tuning and/or calibration that is required. Production control system 110 transmits instructions to the instruments of the automated production system 100 to effect any tuning and/or calibration determined to be necessary or desirable according to analysis of the quality control data.

The principal subsystems of automated production system 100 when configured for synthesis of DNA or RNA include synthesis system 120, cleave system 122, purification system 130, re-plate system 140, quality control system 150, drying system 160, packing system 170, and robotic transport system 180. Subsystems may also be integrated such that one or more subsystems are provided in one piece of equipment. As shown in FIG. 1, for example synthesis system 120 and cleave system 122 may be combined in a single piece of equipment. Furthermore, in order to balance the throughput of each subsystem, one or more subsystems may comprises multiple pieces of the same equipment or different equipment operating in parallel. Multiple pieces of equipment may also be used to provide redundancy such that individual modules may be taken offline for servicing without interrupting operation of the automated production system 100.

Robotic transport system 180 is responsible for moving material between the various subsystems (See FIGS. 4A-4C). Each subsystem has a mechanical interface responsible for receiving material from robotic transport system 180, moving material within the subsystem, and then delivering processed material back to robotic transport system 180. Robotic transport system 180 moves material between the various subsystems under the control of production control system 110. Production control system 110 schedules work in the various subsystems and keeps track of materials during processing. Accordingly, production control system can instruct robotic transport system 180 to retrieve material from one subsystem and more it to another subsystem. Robotic transport system 180 includes for example a number of robot arms, motion platforms, and grippers which allow it to engage materials and move them between the subsystems. Preferably robotic transport system 180 is modular and has redundant components such that servicing of one arm does not interrupt operation of automated production system 100.

Material is transferred between equipment in a component having an array of vessels. The array of vessels may be for example a microplate also known as a microtitre plate or microwell plate. Standard microplates have been defined having 96, 384, and 1536 separate wells for holding materials. Microplate standards with respect to critical dimensions of the microplates and wells are established by the Society For Laboratory Automation and Screening (SLAS) and American National Standards Institute (ANSI). Commercially available equipment and mechanical equipment interfaces are typically designed to handle microplates which meet the relevant standards—Standards ANSI/SLAS 1-2004 through ANSI/SLAS 4-2004. Although standard microplates are typically used in biochemistry, non-standard microplates, and alternative vessel arrays suitable for containing an organized collection of materials or production products may also be used without departing from the scope of the invention. Thus, although the term microplate will be used, for convenience, throughout this application, the term should be understood to include such alternative vessel arrays.

Typically each subsystem of automated production system 100 has a dedicated control system and communications interface. The control systems and communications interfaces may in some cases be custom designed for interaction with production control system 110. More typically however, where subsystems are made by third party vendors and therefore have particular control systems and interfaces. Production control system 110 therefore includes a library of interface modules designed for interacting with the control systems and interfaces of the subsystems.

Synthesis of oligonucleotides is performed in synthesis system 120. Alternative synthesis systems 120 can be used for production of different biopolymers. Standalone oligonucleotide synthesizers are known in the art. However such synthesizers require operation by skilled technicians. Transport of and material and provision of reagents requires constant technical supervision. In embodiments of the present invention an automated modular oligonucleotide synthesizer is provided. Microplates having an array of wells holding functionalized support medium (typical functionalized controlled pore glass “CPG”) are fed into the synthesis system 120 by a robotic transport system 180. Synthesis reagents, power, and gases are fed to the synthesizer from a continuous monitored supply.

Synthesis system 120 comprises a plurality of channels each of which allows for independent synthesis of an oligonucleotide by stepwise extension of the oligonucleotide. In order to control oligonucleotide manufacture the synthesis system provides for stepwise addition of nucleotides to extend the oligonucleotides chains. The system independently controls which nucleotide reagents are added to each vessel of the microplate. For example, synthesis system 120 may comprise having 96, 384, or 1536 independent channels such that a different oligonucleotide can be synthesized in each well of a 96, 384, or 1536 well microplate. Synthesis of particular oligonucleotides and oligonucleotide quantities by synthesis system 120 can be commanded by production control system 110 without human intervention. A plurality of individual synthesizers may be provided operating in parallel as part of synthesis system 120 with production control system 110 responsible for distributing and scheduling the synthesis processes.

Oligonucleotides are synthesized bound to the solid support, e.g. controlled pore glass (CPG), in individual reaction vessels such as the wells of microplates. After completion of synthesis, the reaction products must be cleaved from the CPG. Cleave system 122 provides for cleaving the synthesis products from the CPG. Cleave system 122 can be integrated with synthesis system 120 as shown, or may be a separate piece of equipment if the synthesis system does not have cleaving functionality. Where a separate cleave system 122 is used, the robotic transport system 180 moves the microplate from the synthesizer to the cleavage station automatically. After cleavage, the robotic transport system 180 moves the microplates containing solutions of unpurified synthesis products to the purification system 130.

After cleavage, the synthesis reaction products must be purified in purification system 130. In DNA/RNA synthesis, nucleotides are added sequentially to a molecule. In each extension cycle a small percentage of the molecules will not react. These molecules are capped to prevent further reaction. However, the synthesis reaction products will include molecules of the full intended sequence as well as truncated (shorter) molecules. The purification process separates the desired oligonucleotide products from contaminants (desalting). Purification can also eliminate most of the truncated molecules. Various purification methods may by be implemented by the purification system including Reverse-Phase High Performance Liquid Chromatography (RP-HPLC), Anion-Exchange HPLC, or Gel Filtration, and Polyacrylamide gel electrophoresis (PAGE). The particular purification method is selected based on the properties of the produced oligonucleotides and the desired level of purity. After purification, the robotic transport system 180 moves microplates containing solutions of purified oligonucleotides to a re-plating system 140 for re-plating and quantifying the purified oligonucleotides.

In the re-plating system 140, the purified oligonucleotide is re-plated into shippable microplates for delivery to the customer. Re-plating may include re-plating from one size/type of microplate to e.g. standard 96 well microplates to be provided to the customer. In the re-plating equipment aliquots of the purified oligonucleotides are also removed and passed to one or more mass spectrometry systems for quality control assessment. The re-plating system also includes means for measuring volume and optical absorbance of the oligonucleotide solutions in order to quantify the amount of DNA/RNA present. This information is provided to customer 190 in order that customer 190 may later generate a solution or of a required molarity. The robotic transport system then moves microplates containing solutions of purified oligonucleotide products to a dry down system 160. The robotic transport system also moves duplicate microplates containing the sample aliquots to quality control system 150.

Quality control system 150 includes equipment for assessing the quality of the DNA/RNA products or other biopolymers. Quality control system 150 may include one or more systems for performing mass spectroscopy of the DNA/RNA products. In a preferred embodiment, a combination of electrospray ionization mass spectroscopy (ESI) and matrix assisted laser desorption/ionization (MALDI). The ESI equipment can be used for high throughput screening of all samples whereas MALDI, being low through can be used on a sample population of samples or on samples selected for additional screening based on the ESI results. Quality control system 150 may also be used for analysis of reagents and materials used in the synthesis process. The results of quality control system 150 are provided to production control system 110. The results from quality control system 150 can be used to derive quality information to be provided to customer 190 via customer interface 102.

The results from quality control system 150 can also be used by production control system 110 to monitor and adjust operation of the synthesis and other systems. For example, the quality control results may indicate that one or more channel of synthesis system 120 is no longer synthesizing correctly. Production control system can then adjust operation of synthesis system 120 no longer uses the non-functional channel until after the channel is serviced. Uninterrupted production may however continue on the remaining channels until that service is performed. Additionally, continuous quality control of input reagents and materials and output DNA/RNA products allows for closed loop software control at the system, instrument and channel levels in which the system, instruments, and/or channels may be tuned or calibrated to enhance performance in response to the collected quality control data relevant to the system, instrument or channels. The quality control data can be continuously analyzed by the production control system 110 which can determine tuning and or calibration that is required and transmit instructions to the subsystems of the automated production system 100.

The dry down system 160 comprises an automated vacuum centrifuge system. The vacuum centrifuge automatically controls temperature, spin speed, and vacuum to spin the oligonucleotide to the bottom of the microplate wells and dehydrate the oligonucleotide solutions in the microplate for shipping. After dry down, the robotic transport system 180 then moves the microplates containing dried purified oligonucleotide products to a packaging system 170.

In the packaging system the microplates are sealed by applying an impermeable film over the wells. The microplates are then labeled and packaged for shipping to the customer 190. The package, labeled product is removed from the packaging station by the robotic transport system and can then be distributed from shipping 104 directly to the customer 190.

In addition to the shipped product the customer 190 is also provide with quantization data indicating the amount of oligonucleotide provided and information identifying the sequence of oligonucleotide in each well of the shipping plate. Additionally quality control information derived from mass spectrometry of the sample aliquot of the oligonucleotide is also provided to the customer. The product quantity, sequence, and quality information can be provided to customer 190 automatically via customer interface 102.

Although the automated production system described above is directed to the production of DNA and RNA, the modular system may be readily adapted by substitution or addition of various components to the production and/or analysis of other biopolymers, synthetic polymers, and other molecules where it is necessary or desirable to produce and/or screen a large number of different compounds in an automated and efficient manner. For example, a hybridization or screening process may be added using the existing ESI and/or MALDI equipment in combination with a liquid handling step to add a target molecule to the synthesized DNA/RNA and or Aptamers. Alternatively additional equipment may be added for adding reagents to microplates of synthesized products and then screening/reading the microplates to identify desirable products. In a recursive process, where desirable products are discovered, variations of the desirable products may then be synthesized and assessed to identify more desirable products having better properties/specificity to ‘evolve” synthesis products having desirable properties over several generations. The “evolution process” can be performed in an automated fashion under the control of production control system 110. In alternative embodiments, synthesis system 120 suitable for synthesizing DNA and/or RNA may be substituted with a synthesis system suitable for producing peptides, polymers or other molecules.

In a particular embodiment, the automated system can be used for experimentation in addition to or instead of biopolymer production. Modules in the array can include fluorescent microscopes or scanners, PCR thermocyclers, gel electrophoresis units, shakers and incubators for growing cells, and any other scientific devices and instrumentation configured for integration into the array and control by the production control system. Analogous to how customers place order for production of custom biopolymers, they would place orders for experimental processes—and such orders could range from simple single step experiments like measuring the kinetics of a reaction to complex iterative series of experiments with conditional logic between steps. An iterative series of experiments could comprise, for example: 1) synthesizing a DNA vector with a number of random variations; 2) transfecting populations of cells; 3) measuring expression of the vectors; 4) analyzing a property of interest of the transfected cells; 5) selecting the best performing vector; 6) generating new DNA vector sequences based on the best performing vector; 7) repeating steps 2-6 until certain performance criteria are met; and 8) exiting the cycle when certain performance criteria are met delivering one or more sequence of DNA vectors meeting the performance criteria (and/or synthesized DNA of the identified one or more sequences).

Modular Equipment

As described above, the production process requires the coordinated use of a variety of pieces of equipment and the automated transport of material between the equipment. As described below, the equipment is organized as modules which are provided in an array. In a preferred embodiment the modules are arranged in one or more linear array, however other array topographies may also be used. Modules can be stacked vertically as well as adjacent to each other for a two dimensional array. The modules can be designed to mount to a rack or stack one upon the other. For higher density, parallelism and redundancy, modules can be configured with connections on top, and multiple arrays can be arranged back to back with special modules dedicated to passing materials between the arrays. In this configuration, processes can be routed between arrays in the event of module failure and production can continue uninterrupted without human intervention.

The modules are designed such that they can be easily added to and removed from the array without interrupting the production process in the remaining modules. Connections to the equipment are facilitated by a technician accessible interface accessible from the rear surface of each module while the front surface of each module has an automatic mechanical interface for receiving materials from and returning materials to a robotic transport system for automated transport of materials and products. The array is designed such that the robotic transport system has exclusive access to the front side mechanical interfaces of the modules in a human-free zone. Technician access to the modules for adding, removing, connecting and servicing the modules is made from a separate zone (for example the rear side of a linear array or the outside of a circular array.

FIGS. 2A-2B illustrate examples of modular equipment according to an embodiment of the present invention. The various equipment of the Oligonucleotide synthesis system is provided in modules. Each module provides a rack mountable envelope that encapsulates a piece of equipment used in the oligonucleotide synthesis system.

FIG. 2A shows the front side of an example module 200. As shown in FIG. 2A, the front side 210 of module 200 includes a mechanical interface 212. Mechanical interface 212 is typically a motorized device having a door 214 which extends from and retracts into module 200 in order to receive microplates from the robotic transport system for processing and then redelivering processed microplates to the robotic transport system. Standard motion control systems are available for receiving material via door 214.

The front side 210 of module 200 may also comprise one or more registration points 216 which allows for identification and registration of the robotic transport system with the door 214 of mechanical interface 212. Registration points 216 can be mechanically recognized by the robotic transport system using e.g. a training process. Alternative a robot vision system may identify and locate the registration points. Module 200, may also be provided with mounting features 218 for connecting and securing the module 200 to a rack (not shown). Mounting features 218 may also serve for identification and registration of the robotic transport system with the door 214 of mechanical interface 212 in addition to or as an alternative to registration points 216.

FIG. 2B shows the rear side 220 of an example module 200. As shown in FIG. 2A, the rear side 220 of module 200 includes interface features which allow module 200 be connected by a technician to power, network, gases and fluids. All of the necessary connections for module 200 are provided on the rear side 220 of module 200 such that they can be accessed by a technician. For example, rear side 220 of module 200 includes power connection 222, network connection 224, module purge connection 227, and a plurality of quick connections 226, 228 for gases, reagents, vacuum, water etc. Rear side 220 may also comprise an array of warning and or status lights 225.

FIGS. 2A and 2B show an example of a module 200. Automated production system 100 includes a collection of different modules performing different functions. Each module may be custom designed for use in the automated production system 100 or may comprises commercially available equipment to which has been added a module envelope which adapts the equipment for use in automated production system 100 by providing connections on the rear side, an appropriate robotic transport system interface on the front side and features for mounting the equipment in the modular array.

Automated production system 100 includes, for example: a custom DNA/RNA synthesizer which uses amidite reagents to synthesize DNA/RNA in accordance with sequences and quantities specified in customer orders; and a custom vacuum centrifuge which provides controlled heat and vacuum at high g forces in order to dry down plates of purified DNA/RNA. Automated production system 100 also includes modularized commercially available equipment, including, for example: Tecan Freedom EVO 150; MALDI Bruker—Autoflex Speed; Plate Labeler—BioSero Gecko; Plate Sealer—BioSero Wasp; UV-VIS—BMG Labtech Nano; and Plate Washer—Matrical Squirt. Additional or different equipment may be integrated into the array, including but not limited to synthesis modules for biopolymers other than DNA and RNA, fluorescent microscopes or scanners, PCR thermocyclers, gel electrophoresis units, shakers and incubators for growing cells, and any other scientific devices and instrumentation configured for control by the production control system.

Modular Equipment Array

In a preferred embodiment the equipment making up automated production system 100 including synthesis system 120, cleave system 122, purification system 130, re-plate system 140, quality control system 150, drying system 160, packing system 170 are arranged as a modular equipment array 300 in a rack system 350. Modules can be added, removed from system for maintenance repair without impairing functioning of system or interrupting production. FIGS. 3A and 3B illustrate components and an example layout of a modular equipment array 300 and rack system 350 according to an embodiment of the present invention.

Modules can be stacked vertically as well as adjacent to each other for a two dimensional array. The modules can be designed to mount to a rack or stack one upon the other. For higher density, parallelism and redundancy, modules can be configured with connections on top, and multiple arrays can be arranged back to back with special modules dedicated to passing materials between the arrays. In this configuration, processes can be routed between arrays in the event of module failure and production can continue uninterrupted without human intervention.

FIG. 3A shows a layout for a modular equipment array 300. As shown in FIG. 3A, the modules in vertical groups with the groups arranged in a linear array. Depending on the throughput of each module type there may be only a single module of a particular module type or a plurality of modules of a particular module type operating in parallel. Work is divided between multiple units/scheduled by production control system. The front side 310 of the modular equipment array 300 presents the mechanical interfaces 312 of each module for receiving materials from the robotic transport system and returning materials to the robotic transport system. Preferably the front side of the array requires no technician access. The rear side 320 of modular equipment array 300 presents interfaces which allow a technician to make power, network, gas, and reagent connections (See FIG. 2B). Preferably all consumables are plumbed in from monitored sources which provide a continuous/uninterrupted supply of consumables.

Where multiple units of a particular module type are provided, the modules are designed to be stackable in a rack 350. Preferably rack 350 includes features 352 for securing and registering the presence of a module such that the production control system is notified which modules are present and online at any point in time. Accordingly the production control system is aware of which systems are present, and can adjust for equipment removed/unavailable by routing materials to operating modules using the robotic transport system. Scheduling software can be instructed to take a module offline or put a module online on the fly. The robotic transport system will then no longer service the module and it can be pulled from the rack without having to interrupt the production process. Preferably each rack 350, includes a computer system, cooling, QC system, tracking, system, power supply, and UPS 354 which can be shared by all of the equipment in the rack 350.

To facilitate connections of utilities and reagents to modules in the modular equipment array 300 a supply system is provided to connect the modules to sources of gasses, liquids, power, and vacuum. FIGS. 3C-3E illustrate an embodiment of a supply system designed to facilitate connection of required utilities to modules in modular equipment array 300. FIG. 3C shows the rear side of modular equipment array 300. Each of the modules is provided with a standard format utility interface 360 (see FIG. 3D for detail). Utilities are provided from a series of supply lines 362 which connect to sources of gasses, liquids, power, and vacuum. Manifolds 364 are connected to the supply lines 362 at intervals. Each of the manifolds 364 is also provided with a standard format utility interface (see FIG. 3D for detail).

The use of a standard format utility interface 360 and multi-lumen connector 366 facilitates connection and disconnection of modules allowing for their removal and replacement in the modular equipment array 300. Additionally the standard format utility interface avoids the possibility of user error in connecting the supply lines to the modules. Where separate lines are connected it is possible for a technician to connect the supply lines to the wrong ports of the modules thereby causing at least incorrect operation of the modules but also possibly damaging the modules. The supply lines may be quickly connected to the modules of the equipment array by attaching a multi-lumen connector 366 (see FIG. 3E) to the standard format utility interface 360 of the manifold 364 and the standard format utility interface 360 of the module. The supply lines may also be quickly disconnected from the modules by removing the multi-lumen connector 366.

FIG. 3D shows an example of the standard format utility interface 360. As shown in FIG. 3D, standard format utility interface 360 includes a plurality of ports 370—6 ports are shown in FIG. 3D but a greater or lesser number of ports may be included depending upon the needs of the modules in modular equipment array 300. The ports may be of various types depending upon the type of utility, for example the ports may be quick connect ports for gasses and liquids, and electrical receivers for power and data connections. The ports are arranged in standard order and placement for all modules. Where a module does not require a particular utility, that port is left blank, capped, or plugged however, the arrangement of the other ports is unchanged. Standard format utility interface 360 includes a plurality of fasteners 372 for connecting to the multi-lumen connector 366. Standard format utility interface 360 also includes a registration feature 374, such as a pin which ensures that the multi-lumen connector 366 can only be connected to the standard format utility interface 360 in the correct orientation.

FIG. 3E shows an example of multi-lumen connector 366. Multi-lumen connector includes couplings 380 at each end of a multi-lumen flexible coupling 366. Multi-lumen coupling may include lumens for gasses, liquids, and vacuum, as well as electrical wires for data and power. Couplings 380 are designed to mates with the standard format utility interface 360 in a manner which aligns the ports 370 of couplings 380 with the ports 370 of the standard format utility interface 360. The ports may be of various types depending upon the type of utility, for example the ports may be quick connect ports for gasses and liquids, and electrical receivers for power and data connections and are each designed to mate with the corresponding ports of the standard format utility interface 360. Couplings 380 includes a plurality of fasteners 382 for connecting to the fasteners 372 of the standard format utility interface 360. Couplings 380 also include a registration feature 374, such as a hole which ensures that the multi-lumen connector 366 can only be connected to the standard format utility interface 360 in the correct orientation.

Robotic Transport System

FIGS. 4A-4C show an embodiment 400 of robotic transport system 180 of FIG. 1, for moving materials between subsystems of the automated production system 100 of FIG. 1 according to an embodiment of the present invention. FIG. 4A shows a robotic transport system in combination with a single modular equipment array 300. FIG. 4B shows a robotic transport system in combination with a two modular equipment arrays 300. FIG. 4C shows a robotic arm component of the robotic transport system.

Referring to FIG. 4A which shows a robotic transport system 400 in combination with a single modular equipment array 300. The robotic transport system 400 moves materials between machine operable interfaces of the various pieces of equipment in the modular equipment array under the control of the production control system. Transport of material on robotic transport system side performed without human intervention. The robotic transport system includes a gantry 410 and two or more robot arms 420.

The gantry 410 provides for independent linear movement of the robot arms 420 along a track or tracks 412 such that the robot arms may be aligned with any equipment of the modular equipment array 300. The robot arms 420 provide multiple degrees of freedom such that they can interact with the mechanical interface of any equipment in the modular equipment array 300 when appropriately position on gantry 410. Two or more robot arms 420 are provided to allow multiple simultaneous actions and redundancy in case of failure. The arms are also modular such that they can be removed, repaired and replaced without interruption operation of the automated production system.

FIG. 4A shows the working envelope 430 of the robotic transport system. As shown in FIG. 4A, the working envelope 430 encompasses the mechanical interfaces of all the equipment in the modular equipment array 300. Robotic transport system 400 has sufficient range of motion to access all material interfaces of modular equipment array 300. The working envelope 430 is typically preserved as a human-free zone, either by fences, barriers or warnings, such that the robot transport system operates without obstruction and contamination in the zone where materials are transported is minimized. In some cases, the working envelope is sealed or partially sealed from the remaining lab space to form a separate clean room to reduce contamination and/or maintain a controlled environment for the equipment and reactions—e.g. by controlling or limiting the oxygen and moisture in the working envelope. As previously described, technician access is limited to the rear side 432 of modular equipment array 300 where all the interfaces are provided for connecting and servicing the equipment.

FIG. 4B shows an alternative arrangement where robotic transport system 400 operates in conjunction with two modular equipment arrays 300. The robotic transport system includes a gantry 410 and two or more robot arms 420. Robotic transport system 400 has sufficient range of motion to access all material interfaces of both modular equipment arrays 300. The working envelope 430 is typically preserved as a human-free zone, either by fences, barriers or warnings, such that the robot transport system operates without obstruction and contamination in the zone where materials are transported is minimized. In some cases, the working envelope 430 is sealed or partially sealed from the remaining lab space to form a separate clean room to reduce contamination. As previously described, technician access is limited to the rear side 432 of each modular equipment array 300 where all the interfaces are provided for connecting and servicing the equipment.

Robotic transport system 400 may automatically detects/register the mechanical interfaces of equipment modules present in modular equipment array 300. This registration may be achieved for example by notification of the presence of a piece of equipment in a rack in combinations with a stored record of the position of the mechanical interface in the piece of equipment. When a new rack is set up, the position and orientation of a local rack coordinate system is defines relative to the robotic transport system by having the tip of the robot arm probe orientation points on the rack. The position of all modules and their mechanical interfaces can then be precisely defined relative to the coordinate system. The production control system has internal models of the mechanical interfaces of the equipment such that after defining the coordinate system of the rack the production control system can find each mechanical interface with the robotic transport system. Alternatively, the robotic transport system may be trained as to mechanical interface location using mechanical and/or visual registration features provided on the equipment.

FIG. 4C shows an enlarged view of a robot arm 420. As shown in FIG. 4C, robot arm 420 includes a gripper mechanism 422 designed to engage and release a microplate 450 in order to move a microplate 450 between the mechanical interfaces of different pieces of equipment. Robot arm 420 includes a base 424 adapted to be mounted to the gantry 410. Between bases 424 and gripper mechanism are a plurality of linkages 426 and joints 428 which allow the robot arm to move the gripper mechanism 422 relative to the base 424 with sufficient degrees of freedom and range of motion in order to access microplates at the mechanical interfaces of different pieces of equipment in the modular equipment array. Preferably, robot arm 420 is a commercially available 6 degree of freedom robot arm having a sufficiently large range of motion to reach all mechanical interfaces within the desired working envelope 430 when combined with the linear movement provided by gantry 410.

As shown in FIG. 1, robotic transport system 180 of which robotic transport system 400 is an example, operates under control of production control system 110. Production control system 110 schedules operations of the equipment in the modular equipment array 300 and operates the robotic transport system 180 to move materials between different pieces of equipment. Production control system 110 is notified when equipment is added to or removed from the modular equipment array 300 and can adjust scheduling of equipment operation and movement by robotic transport system 180 to adjust for missing/unavailable equipment.

The foregoing description of preferred embodiments of the present invention has been provided for the purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many embodiments were chosen and described in order to best explain the principles of the invention and its practical application, thereby enabling others skilled in the art to understand the invention for various embodiments and with various modifications that are suited to the particular use contemplated. Although the modular system described is directed to the production of DNA and RNA, the modular system may be readily adapted by substitution or addition of various components to the production and/or analysis of a wide range of biopolymers where it is necessary or desirable to produce and/or analyze a large number of different compounds in an automated and efficient manner. It is intended that the scope of the invention be defined by the claims and their equivalents.

Claims (20)

What is claimed is:
1. An automated production system comprising:
a production control system which controls production in an automated oligonucleotide production process;
a plurality of equipment modules for processing materials under control of the production control system, wherein each equipment module comprises on a front side a mechanical interface for receiving materials and transmitting processed materials, and, on a rear side, an interface for connecting power, network, and any required reagents;
wherein the plurality of equipment modules includes:
an oligonucleotide synthesis system and one or more of,
an oligonucleotide purification system,
an oligonucleotide quantization system,
an oligonucleotide quality control system, and
a packaging/labeling system;
a linear array in which the plurality of equipment modules is secured such that the mechanical interfaces are accessible from a front side of the linear array and all the interfaces are accessible from a rear side of the linear array; and
a robotic transport system positioned adjacent to the front side of the linear array, wherein the robotic transport system includes a plurality of robot arms adapted to move processed materials between the mechanical interfaces of the plurality of equipment modules under the control of the production control system;
whereby oligonucleotides can be automatically synthesized and processed by the plurality of equipment modules under control of the production control system.
2. The automated production system of claim 1, wherein;
the robotic transport system and the front side of the linear array is secured as a human-free zone; and
technician access to the linear array is limited, during operation of the automated production system, to the rear side of the linear array.
3. The automated production system of claim 1, wherein the plurality of equipment modules are hot-swappable under control of the production control system such that individual equipment modules may be deactivated and removed from the linear array for servicing without interruption to the automated production process.
4. The automated production system of claim 1, wherein the robotic transport system comprises a gantry system for moving the robot arms in a direction parallel to the linear array of equipment modules such that the robot arms can access the mechanical interfaces of the plurality of equipment modules.
5. The automated production system of claim 1, wherein the oligonucleotide production process is one of a DNA synthesis and an RNA synthesis process.
6. The automated production system of claim 1, further comprising:
a customer interface for receiving production orders from customers and providing production orders to the production control system whereby the production control system can control production of oligonucleotides in the automated oligonucleotide production process in response to said production orders received from customers via the customer interface.
7. An automated production system comprising:
a production control system which controls an automated oligonucleotide production process;
a plurality of equipment modules which process materials under control of the production control system, wherein each equipment module comprises a mechanical interface for receiving materials and transmitting processed materials, a system interface for connecting power, network, and any required fluids, and reagents;
wherein the plurality of equipment modules includes:
an oligonucleotide synthesis system and one or more of,
an oligonucleotide purification system,
an oligonucleotide quantization system,
an oligonucleotide quality control system, and
a packaging/labeling system;
an array in which the plurality of equipment modules is arranged and secured such that the mechanical interfaces are accessible from a front side of the array; and
a robotic transport system positioned adjacent to the front side of the array, wherein the robotic transport system includes one or more robot arms adapted to move materials and processed materials between the mechanical interfaces of the plurality of equipment modules under the control of the production control system;
whereby oligonucleotides can be automatically synthesized and processed by the plurality of equipment modules under control of the production control system.
8. The automated production system of claim 7, wherein the robotic transport system and the front side of the array is secured as a human-free zone.
9. The automated production system of claim 7, wherein the plurality of equipment modules are hot-swappable under control of the production control system such that individual equipment modules may be deactivated and removed from the array for servicing without interruption to the automated production process.
10. The automated production system of claim 7, wherein the oligonucleotide production process is one of a DNA synthesis process and an RNA synthesis process.
11. The automated production system of claim 7, further comprising:
a customer interface connected to the production control system wherein the customer interface receives oligonucleotide production orders including sequence information from customers and provides oligonucleotide production information to the production control system whereby oligonucleotides having sequences specified by the oligonucleotide sequence information in the oligonucleotide production orders can be automatically synthesized and processed by the plurality of equipment modules under control of the production control system.
12. The automated production system of claim 7, wherein the plurality of equipment modules includes an oligonucleotide synthesis system, an oligonucleotide purification system, an oligonucleotide quality control system, an oligonucleotide re-plating system, and a centrifuge system for oligonucleotide dry down, whereby oligonucleotides can be automatically synthesized and processed by the plurality of equipment modules under control of the production control system.
13. The automated production system of claim 12, wherein the automated production system is configured for production of DNA oligonucleotides.
14. The automated production system of claim 12, wherein the automated production system is configured for production of RNA oligonucleotides.
15. An automated production system comprising:
a production control system which controls production in an automated oligonucleotide production process;
a plurality of equipment modules which process materials under control of the production control system wherein the plurality of equipment modules includes:
an oligonucleotide synthesis system and one or more of,
an oligonucleotide cleavage system
an oligonucleotide purification system,
an oligonucleotide quantization system,
an oligonucleotide quality control system,
an oligonucleotide re-plating system,
a centrifuge system for oligonucleotide dry down, and
a packaging/labeling system;
wherein each equipment module comprises a mechanical interface for receiving materials and transmitting processed materials, and, a system interface which provides power, communication with the production control system, and any required reagents;
a robotic transport system including one or more robotic arms adapted to move processed materials between the mechanical interfaces of the plurality of equipment modules under the control of the production control system; and
an array in which the plurality of equipment modules is arranged adjacent to the robotic transport system such that the mechanical interfaces are accessible by the one or more robotic arms;
whereby oligonucleotides can be automatically synthesized and processed by the plurality of equipment modules under control of the production control system.
16. The automated production system of claim 15, wherein the robotic transport system is secured as a human-free zone.
17. The automated production system of claim 15, wherein the plurality of equipment modules are hot-swappable under control of the production control system such that individual equipment modules may be deactivated and removed from the array for servicing without interruption to the automated production process.
18. The automated production system of claim 15, further comprising:
a customer interface connected to the production control system wherein the customer interface receives oligonucleotide production orders including oligonucleotide sequence information from customers and provides oligonucleotide production information to the production control system whereby oligonucleotide having sequences specified by the oligonucleotide sequence information in the oligonucleotide production orders can be automatically synthesized and processed by the plurality of equipment modules under control of the production control system.
19. The automated production system of claim 16, wherein the oligonucleotide production process is a DNA oligonucleotide synthesis process and the plurality of equipment modules includes a DNA oligonucleotide synthesis system, a DNA oligonucleotide purification system, and one or more of a DNA oligonucleotide cleavage system, a DNA oligonucleotide quality control system, a DNA oligonucleotide re-plating system, a centrifuge system for DNA oligonucleotide dry down, and a packaging and labeling system.
20. The automated production system of claim 16, wherein the oligonucleotide production process is an RNA oligonucleotide synthesis process and the plurality of equipment modules includes an RNA oligonucleotide synthesis system, an RNA oligonucleotide purification system, and one or more of an RNA oligonucleotide cleavage system, an RNA oligonucleotide quality control system, an RNA oligonucleotide re-plating system, a centrifuge system for RNA oligonucleotide dry down, and a packaging and labeling system.
US14/866,091 2014-09-25 2015-09-25 Automated modular system and method for production of biopolymers Active 2036-10-14 US10040048B1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US201462055419P true 2014-09-25 2014-09-25
US14/866,091 US10040048B1 (en) 2014-09-25 2015-09-25 Automated modular system and method for production of biopolymers

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US14/866,091 US10040048B1 (en) 2014-09-25 2015-09-25 Automated modular system and method for production of biopolymers
US16/027,982 US20180311637A1 (en) 2014-09-25 2018-07-05 Automated modular system and method for production of biopolymers

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/027,982 Continuation US20180311637A1 (en) 2014-09-25 2018-07-05 Automated modular system and method for production of biopolymers

Publications (1)

Publication Number Publication Date
US10040048B1 true US10040048B1 (en) 2018-08-07

Family

ID=63013597

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/866,091 Active 2036-10-14 US10040048B1 (en) 2014-09-25 2015-09-25 Automated modular system and method for production of biopolymers
US16/027,982 Pending US20180311637A1 (en) 2014-09-25 2018-07-05 Automated modular system and method for production of biopolymers

Family Applications After (1)

Application Number Title Priority Date Filing Date
US16/027,982 Pending US20180311637A1 (en) 2014-09-25 2018-07-05 Automated modular system and method for production of biopolymers

Country Status (1)

Country Link
US (2) US10040048B1 (en)

Citations (109)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5368823A (en) 1993-02-11 1994-11-29 University Of Georgia Research Foundation, Inc. Automated synthesis of oligonucleotides
US5472672A (en) 1993-10-22 1995-12-05 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US5474796A (en) 1991-09-04 1995-12-12 Protogene Laboratories, Inc. Method and apparatus for conducting an array of chemical reactions on a support surface
US5554501A (en) 1992-10-29 1996-09-10 Beckman Instruments, Inc. Biopolymer synthesis using surface activated biaxially oriented polypropylene
US5604097A (en) 1994-10-13 1997-02-18 Spectragen, Inc. Methods for sorting polynucleotides using oligonucleotide tags
US5614608A (en) 1995-01-20 1997-03-25 Selectide Corporation Apparatus and method for multiple synthesis of organic compounds on polymer support
US5643738A (en) 1994-11-10 1997-07-01 David Sarnoff Research Center, Inc. Method of synthesis of plurality of compounds in parallel using a partitioned solid support
US5681534A (en) 1995-07-20 1997-10-28 Neves; Richard S. High throughput oligonucleotide synthesizer
US5716584A (en) 1995-09-07 1998-02-10 Pathogenesis Corporation Device for the synthesis of compounds in an array
US5750341A (en) 1995-04-17 1998-05-12 Lynx Therapeutics, Inc. DNA sequencing by parallel oligonucleotide extensions
US5750672A (en) 1996-11-22 1998-05-12 Barrskogen, Inc. Anhydrous amine cleavage of oligonucleotides
US5766556A (en) 1992-10-08 1998-06-16 Warner-Lambert Company Apparatus and method for multiple simultaneous synthesis
US5770157A (en) 1995-04-17 1998-06-23 Ontogen Corporation Methods and apparatus for the generation of chemical libraries
US5846719A (en) 1994-10-13 1998-12-08 Lynx Therapeutics, Inc. Oligonucleotide tags for sorting and identification
US5865224A (en) 1996-12-20 1999-02-02 Life Technologies, Inc. Method and apparatus for automated dispensing
US5888830A (en) 1995-09-22 1999-03-30 Berlex Laboratories, Inc. Apparatus and process for multiple chemical reactions
US5981733A (en) 1996-09-16 1999-11-09 Incyte Pharmaceuticals, Inc. Apparatus for the chemical synthesis of molecular arrays
US6001311A (en) 1997-02-05 1999-12-14 Protogene Laboratories, Inc. Apparatus for diverse chemical synthesis using two-dimensional array
US6013445A (en) 1996-06-06 2000-01-11 Lynx Therapeutics, Inc. Massively parallel signature sequencing by ligation of encoded adaptors
US6022963A (en) 1995-12-15 2000-02-08 Affymetrix, Inc. Synthesis of oligonucleotide arrays using photocleavable protecting groups
US6024925A (en) * 1997-01-23 2000-02-15 Sequenom, Inc. Systems and methods for preparing low volume analyte array elements
US6033631A (en) 1997-04-28 2000-03-07 Chiron Corporation Synthesizer with reagent recycling
US6040193A (en) 1991-11-22 2000-03-21 Affymetrix, Inc. Combinatorial strategies for polymer synthesis
US6042789A (en) 1996-10-23 2000-03-28 Glaxo Group Limited System for parallel synthesis of organic compounds
US6045755A (en) 1997-03-10 2000-04-04 Trega Biosciences,, Inc. Apparatus and method for combinatorial chemistry synthesis
US6054325A (en) 1996-12-02 2000-04-25 Glaxo Wellcom Inc. Method and apparatus for transferring and combining distinct chemical compositions with reagents
US6080318A (en) 1996-09-25 2000-06-27 Analyticon Ag Biotechnologie Pharmazie HPLC-based device and method for separating high complex substance mixtures
US6083682A (en) 1997-12-19 2000-07-04 Glaxo Group Limited System and method for solid-phase parallel synthesis of a combinatorial collection of compounds
US6121054A (en) 1997-11-19 2000-09-19 Trega Biosciences, Inc. Method for separation of liquid and solid phases for solid phase organic syntheses
US6126904A (en) 1997-03-07 2000-10-03 Argonaut Technologies, Inc. Apparatus and methods for the preparation of chemical compounds
US6143252A (en) 1999-04-12 2000-11-07 The Perkin-Elmer Corporation Pipetting device with pipette tip for solid phase reactions
US6149869A (en) 1996-10-23 2000-11-21 Glaxo Wellcome Inc. Chemical synthesizers
US6171797B1 (en) 1999-10-20 2001-01-09 Agilent Technologies Inc. Methods of making polymeric arrays
US6267930B1 (en) 1997-09-22 2001-07-31 Waldemar Ruediger Apparatus for synthesis of multiple organic compounds with pinch valve block
US6270730B1 (en) 1998-06-16 2001-08-07 Northwest Engineering Inc. Multi-well rotary synthesizer
US20010028866A1 (en) 1994-09-21 2001-10-11 Isis Pharmaceuticals, Inc. Chemical synthesis apparatus employing a droplet generator
US6329210B1 (en) 1999-10-29 2001-12-11 Agilent Technologies, Inc. Method and apparatus for high volume polymer synthesis
US6346423B1 (en) 1999-07-16 2002-02-12 Agilent Technologies, Inc. Methods and compositions for producing biopolymeric arrays
US20020031833A1 (en) 1998-12-22 2002-03-14 Herbert Heyneker Apparatus and method for concurrent chemical synthesis
US20020044894A1 (en) 1999-12-13 2002-04-18 Michal Lebl Oligonucleotide synthesizer
US20020123133A1 (en) 1998-06-08 2002-09-05 Caliper Technologies Corporation Microfluidic matrix localization apparatus and methods
US20020142341A1 (en) * 2001-03-28 2002-10-03 Makoto Kameyama Method and apparatus for producing probe carrier
US20020142454A1 (en) 2001-01-26 2002-10-03 Third Wave Technologies, Inc. Nucleic acid synthesizers
US20020176811A1 (en) 2001-05-16 2002-11-28 Konan Peck Apparatus and methods for chemical synthesis
US6518067B1 (en) 1997-02-17 2003-02-11 Gesellschaft Fuer Biotechnologische Forschung Mbh (Gbf) Automated chemical synthesis apparatus
US6532978B1 (en) 1998-11-20 2003-03-18 Sepiatec Gmbh Method and device for regulating individual sub-flows of a system for conveying fluid media
US20030086829A1 (en) 2001-10-24 2003-05-08 Livesay Eric A. High throughput chemical synthesizer
US20030113237A1 (en) 2001-08-15 2003-06-19 Third Wave Technologies, Inc. Polymer synthesizer
US20030182068A1 (en) 2001-10-30 2003-09-25 Battersby Bronwyn J. Device and methods for directed synthesis of chemical libraries
US20030223909A1 (en) 2000-02-03 2003-12-04 Cellular Process Chemistry, Inc. Scalable continuous production system
US6663832B2 (en) 1999-12-13 2003-12-16 Illumina, Inc. Oligonucleotide synthesizer
US20040132040A1 (en) 2000-11-16 2004-07-08 Hamill Brendan James Polynucleotide analysis using combinatorial pcr
US20040151628A1 (en) * 2001-05-03 2004-08-05 Honkanen Peter D High throughput microarray spotting system and method
US20040241998A1 (en) * 1999-01-22 2004-12-02 Hanson Kyle M. System for processing a workpiece
US6846454B2 (en) 2001-12-24 2005-01-25 Agilent Technologies, Inc. Fluid exit in reaction chambers
US6911151B1 (en) 1998-11-20 2005-06-28 Sepiatec Gmbh Device and method for the parallel separation of substances by liquid chromatography
US20050169816A1 (en) 2003-12-15 2005-08-04 Kirshner Brian M. Automated oligomer synthesis
US6932943B1 (en) 2001-01-26 2005-08-23 Third Wave Technologies Nucleic acid synthesizers
US20050244885A1 (en) 2000-07-31 2005-11-03 Wolber Paul K Array based methods for synthesizing nucleic acid mixtures
US20060182609A1 (en) * 2004-11-23 2006-08-17 Guerra Lawrence E Robotic arm for use with pharmaceutical unit of use transport and storage system
US7115400B1 (en) 1998-09-30 2006-10-03 Solexa Ltd. Methods of nucleic acid amplification and sequencing
US20070096674A1 (en) * 2005-10-28 2007-05-03 Fanuc Ltd Robot control device
US20070110638A1 (en) 2005-09-14 2007-05-17 Heiner David L Continuous polymer synthesizer
US20070128084A1 (en) 1996-01-16 2007-06-07 Affymetrix, Inc. Analytical Biochemistry System with Robotically Carried Bioarray
US7249529B2 (en) 2003-03-28 2007-07-31 Protedyne Corporation Robotically manipulable sample handling tool
US20070276965A1 (en) * 2006-05-03 2007-11-29 Data I/O Corporation Automated programming system employing smart interfaces
US7321828B2 (en) 1998-04-13 2008-01-22 Isis Pharmaceuticals, Inc. System of components for preparing oligonucleotides
US20080038724A9 (en) 2002-03-01 2008-02-14 Integrated Dna Technologies, Inc. Methods for amplifying polymeric nucleic acids
US20080058512A1 (en) 2006-08-31 2008-03-06 Leproust Eric M Apparatuses and methods for oligonucleotide preparation
US20080058511A1 (en) 2006-08-31 2008-03-06 John Hargreaves Methods and compositions useful in the preparation of oligonucleotides
US7411061B2 (en) 2001-10-31 2008-08-12 Agilent Technologies, Inc. Method of synthesizing polynucleotides using ionic liquids
US7413714B1 (en) 2000-07-16 2008-08-19 Ymc Co. Ltd. Sequential reaction system
US20080261220A1 (en) 2000-11-30 2008-10-23 Third Wave Technologies, Inc. Nucleic Acid Detection Assays
US20090148353A1 (en) 2007-12-07 2009-06-11 Thomas Downing Polymer Synthesizer
US7604996B1 (en) 1999-08-18 2009-10-20 Illumina, Inc. Compositions and methods for preparing oligonucleotide solutions
US7647186B2 (en) 2004-12-07 2010-01-12 Illumina, Inc. Oligonucleotide ordering system
US20100248981A1 (en) * 2009-03-27 2010-09-30 Affymetrix, Inc. System and methods for processing microarrays
US20100273264A1 (en) * 2007-09-24 2010-10-28 Timothy Stout Apparatus for and method of preparing plant tissue for plant production
US20110123411A1 (en) 2004-06-30 2011-05-26 Life Technologies Corporation Synthesis of oligomers in arrays
US20110172127A1 (en) 2008-08-27 2011-07-14 Westemd Asset Clearinghouse Company, LLC Methods and Devices for High Fidelity Polynucleotide Synthesis
USRE43097E1 (en) 1994-10-13 2012-01-10 Illumina, Inc. Massively parallel signature sequencing by ligation of encoded adaptors
US8198028B2 (en) 2008-07-02 2012-06-12 Illumina Cambridge Limited Using populations of beads for the fabrication of arrays on surfaces
US20120220497A1 (en) 2009-11-03 2012-08-30 Gen 9, Inc. Methods and Microfluidic Devices for the Manipulation of Droplets in High Fidelity Polynucleotide Assembly
US20120308346A1 (en) * 2011-06-03 2012-12-06 Arthur Keigler Parallel single substrate processing system loader
US8450107B1 (en) 2011-11-30 2013-05-28 The Broad Institute Inc. Nucleotide-specific recognition sequences for designer TAL effectors
US8575071B2 (en) 2010-11-03 2013-11-05 Illumina, Inc. Reducing adapter dimer formation
US20130296192A1 (en) 2010-11-12 2013-11-07 Gen9, Inc. Protein Arrays and Methods of Using and Making the Same
US8697359B1 (en) 2012-12-12 2014-04-15 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products
US8784745B2 (en) 2007-06-21 2014-07-22 Gen-Probe Incorporated Methods for manipulating liquid substances in multi-chambered receptacles
US8795965B2 (en) 2012-12-12 2014-08-05 The Broad Institute, Inc. CRISPR-Cas component systems, methods and compositions for sequence manipulation
WO2014131833A1 (en) 2013-02-27 2014-09-04 Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) Gene editing in the oocyte by cas9 nucleases
US20140273233A1 (en) 2013-03-15 2014-09-18 Sigma-Aldrich Co., Llc Crispr-based genome modification and regulation
US20140274809A1 (en) 2013-03-15 2014-09-18 Integrated Dna Technologies, Inc. Multi-well manifold assembly system for oligonucleotide synthesis
US8865406B2 (en) 2012-12-12 2014-10-21 The Broad Institute Inc. Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation
US8889356B2 (en) 2012-12-12 2014-11-18 The Broad Institute Inc. CRISPR-Cas nickase systems, methods and compositions for sequence manipulation in eukaryotes
US20140357530A1 (en) 2012-12-12 2014-12-04 The Broad Institute Inc. Functional genomics using crispr-cas systems, compositions, methods, knock out libraries and applications thereof
US8906616B2 (en) 2012-12-12 2014-12-09 The Broad Institute Inc. Engineering of systems, methods and optimized guide compositions for sequence manipulation
US20150071889A1 (en) 2013-04-04 2015-03-12 President And Fellows Of Harvard College THERAPEUTIC USES OF GENOME EDITING WITH CRISPR/Cas SYSTEMS
US8993233B2 (en) 2012-12-12 2015-03-31 The Broad Institute Inc. Engineering and optimization of systems, methods and compositions for sequence manipulation with functional domains
US9040678B2 (en) 2011-08-05 2015-05-26 Illumina, Inc. Functionalization and purification of molecules by reversible group exchange
US9069358B2 (en) 2013-06-24 2015-06-30 Biolytic Lab Performance, Inc. System for controlling and optimizing reactions in solid phase synthesis of small molecules
US9073033B2 (en) 2010-01-19 2015-07-07 Illumina, Inc. Methods and compositions for processing chemical reactions
US9115348B2 (en) 2010-05-10 2015-08-25 The Regents Of The University Of California Endoribonuclease compositions and methods of use thereof
US9150896B2 (en) 2012-09-06 2015-10-06 Illumina, Inc. Nucleotides and primers with removable blocking groups
US20150369267A1 (en) 2010-10-08 2015-12-24 Integrated Dna Technologies, Inc. Well drain system for use with multi-well synthesizer
US9238671B2 (en) 2011-01-28 2016-01-19 Illumina, Inc. Oligonucleotide replacement for di-tagged and directional libraries
US9322063B2 (en) 2007-01-26 2016-04-26 Illumina, Inc. Efficient biomolecule recycling method and system
US9370551B2 (en) 2011-07-27 2016-06-21 The Broad Institute, Inc. Compositions and methods of treating head and neck cancer
US9492820B2 (en) 2003-09-19 2016-11-15 Applied Biosystems, Llc High density plate filler

Patent Citations (174)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5474796A (en) 1991-09-04 1995-12-12 Protogene Laboratories, Inc. Method and apparatus for conducting an array of chemical reactions on a support surface
US6040193A (en) 1991-11-22 2000-03-21 Affymetrix, Inc. Combinatorial strategies for polymer synthesis
US5766556A (en) 1992-10-08 1998-06-16 Warner-Lambert Company Apparatus and method for multiple simultaneous synthesis
US5554501A (en) 1992-10-29 1996-09-10 Beckman Instruments, Inc. Biopolymer synthesis using surface activated biaxially oriented polypropylene
US5368823A (en) 1993-02-11 1994-11-29 University Of Georgia Research Foundation, Inc. Automated synthesis of oligonucleotides
US8084245B2 (en) 1993-10-22 2011-12-27 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US7858364B2 (en) 1993-10-22 2010-12-28 The Board Of Trustees Of Leland Junior Stanford University Apparatus and method for polymer synthesis using arrays
US5529756A (en) 1993-10-22 1996-06-25 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US20090054605A1 (en) 1993-10-22 2009-02-26 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and Method for Polymer Synthesis Using Arrays
US5472672A (en) 1993-10-22 1995-12-05 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and method for polymer synthesis using arrays
US20050281719A1 (en) 1993-10-22 2005-12-22 Brennan Thomas M Apparatus and method for polymer synthesis using arrays
US20030069411A1 (en) 1993-10-22 2003-04-10 Brennan Thomas M. Apparatus and method for polymer synthesis using arrays
US5814700A (en) 1993-10-22 1998-09-29 The Board Of Trustees Of The Leland Stanford Junior University Method for polymer synthesis in a reaction well
US20110124529A1 (en) 1993-10-22 2011-05-26 The Board Of Trustees Of The Leland Stanford Junior University Apparatus and Method for Polymer Synthesis Using Arrays
US20010028866A1 (en) 1994-09-21 2001-10-11 Isis Pharmaceuticals, Inc. Chemical synthesis apparatus employing a droplet generator
US5846719A (en) 1994-10-13 1998-12-08 Lynx Therapeutics, Inc. Oligonucleotide tags for sorting and identification
USRE43097E1 (en) 1994-10-13 2012-01-10 Illumina, Inc. Massively parallel signature sequencing by ligation of encoded adaptors
US5604097A (en) 1994-10-13 1997-02-18 Spectragen, Inc. Methods for sorting polynucleotides using oligonucleotide tags
US5643738A (en) 1994-11-10 1997-07-01 David Sarnoff Research Center, Inc. Method of synthesis of plurality of compounds in parallel using a partitioned solid support
US5614608A (en) 1995-01-20 1997-03-25 Selectide Corporation Apparatus and method for multiple synthesis of organic compounds on polymer support
US5770157A (en) 1995-04-17 1998-06-23 Ontogen Corporation Methods and apparatus for the generation of chemical libraries
US5750341A (en) 1995-04-17 1998-05-12 Lynx Therapeutics, Inc. DNA sequencing by parallel oligonucleotide extensions
US6306597B1 (en) 1995-04-17 2001-10-23 Lynx Therapeutics, Inc. DNA sequencing by parallel oligonucleotide extensions
US5969119A (en) 1995-04-17 1999-10-19 Lynx Therapeutics, Inc. DNA sequencing by parallel olgonucleotide extensions
US5681534A (en) 1995-07-20 1997-10-28 Neves; Richard S. High throughput oligonucleotide synthesizer
US5716584A (en) 1995-09-07 1998-02-10 Pathogenesis Corporation Device for the synthesis of compounds in an array
US5888830A (en) 1995-09-22 1999-03-30 Berlex Laboratories, Inc. Apparatus and process for multiple chemical reactions
US6274091B1 (en) 1995-09-22 2001-08-14 Berlex Laboratories, Inc. Apparatus and process for multiple chemical reactions
US6022963A (en) 1995-12-15 2000-02-08 Affymetrix, Inc. Synthesis of oligonucleotide arrays using photocleavable protecting groups
US20070128084A1 (en) 1996-01-16 2007-06-07 Affymetrix, Inc. Analytical Biochemistry System with Robotically Carried Bioarray
US6013445A (en) 1996-06-06 2000-01-11 Lynx Therapeutics, Inc. Massively parallel signature sequencing by ligation of encoded adaptors
US5981733A (en) 1996-09-16 1999-11-09 Incyte Pharmaceuticals, Inc. Apparatus for the chemical synthesis of molecular arrays
US6080318A (en) 1996-09-25 2000-06-27 Analyticon Ag Biotechnologie Pharmazie HPLC-based device and method for separating high complex substance mixtures
US6051439A (en) 1996-10-23 2000-04-18 Glaxo Wellcome Inc. Methods for parallel synthesis of organic compounds
US6042789A (en) 1996-10-23 2000-03-28 Glaxo Group Limited System for parallel synthesis of organic compounds
US6149869A (en) 1996-10-23 2000-11-21 Glaxo Wellcome Inc. Chemical synthesizers
US6117397A (en) 1996-10-23 2000-09-12 Glaxo Group Limited System and methods for parallel synthesis of organic compounds
US5750672A (en) 1996-11-22 1998-05-12 Barrskogen, Inc. Anhydrous amine cleavage of oligonucleotides
US6054325A (en) 1996-12-02 2000-04-25 Glaxo Wellcom Inc. Method and apparatus for transferring and combining distinct chemical compositions with reagents
US5865224A (en) 1996-12-20 1999-02-02 Life Technologies, Inc. Method and apparatus for automated dispensing
US6024925A (en) * 1997-01-23 2000-02-15 Sequenom, Inc. Systems and methods for preparing low volume analyte array elements
US6001311A (en) 1997-02-05 1999-12-14 Protogene Laboratories, Inc. Apparatus for diverse chemical synthesis using two-dimensional array
US6518067B1 (en) 1997-02-17 2003-02-11 Gesellschaft Fuer Biotechnologische Forschung Mbh (Gbf) Automated chemical synthesis apparatus
US6126904A (en) 1997-03-07 2000-10-03 Argonaut Technologies, Inc. Apparatus and methods for the preparation of chemical compounds
US6045755A (en) 1997-03-10 2000-04-04 Trega Biosciences,, Inc. Apparatus and method for combinatorial chemistry synthesis
US6033631A (en) 1997-04-28 2000-03-07 Chiron Corporation Synthesizer with reagent recycling
US6267930B1 (en) 1997-09-22 2001-07-31 Waldemar Ruediger Apparatus for synthesis of multiple organic compounds with pinch valve block
US6121054A (en) 1997-11-19 2000-09-19 Trega Biosciences, Inc. Method for separation of liquid and solid phases for solid phase organic syntheses
US6168914B1 (en) 1997-12-19 2001-01-02 Glaxo Wellcome Inc. System and method for solid-phase parallel synthesis of a combinatorial collection of compounds
US6083682A (en) 1997-12-19 2000-07-04 Glaxo Group Limited System and method for solid-phase parallel synthesis of a combinatorial collection of compounds
US7321828B2 (en) 1998-04-13 2008-01-22 Isis Pharmaceuticals, Inc. System of components for preparing oligonucleotides
US20020123133A1 (en) 1998-06-08 2002-09-05 Caliper Technologies Corporation Microfluidic matrix localization apparatus and methods
US7192558B2 (en) 1998-06-16 2007-03-20 Mcluen Design, Inc. Multi-well rotary synthesizer
US20010051114A1 (en) 1998-06-16 2001-12-13 Mcluen Gary R. Multi-well rotary synthesizer
US8158085B2 (en) 1998-06-16 2012-04-17 Mcluen Design, Inc. Multi-well rotary synthesizer
US6270730B1 (en) 1998-06-16 2001-08-07 Northwest Engineering Inc. Multi-well rotary synthesizer
US8404196B2 (en) 1998-06-16 2013-03-26 Mcluen Design, Inc. Multi-well rotary synthesizer
US8747780B2 (en) 1998-06-16 2014-06-10 Mcluen Design, Inc. Multi-well rotary synthesizer
US6811755B2 (en) 1998-06-16 2004-11-02 Mcluen Design, Inc. Multi-well rotary synthesizer
US7150998B2 (en) 1998-06-16 2006-12-19 Mcluen Design, Inc. Multi-well rotary synthesizer
US8147776B2 (en) 1998-06-16 2012-04-03 Mcluen Design, Inc. Multi-well rotary synthesizer
US9297006B2 (en) 1998-09-30 2016-03-29 Illumina, Inc. Methods of nucleic acid amplification and sequencing
US8652810B2 (en) 1998-09-30 2014-02-18 Illumina, Inc. Methods of nucleic acid amplification and sequencing
US7115400B1 (en) 1998-09-30 2006-10-03 Solexa Ltd. Methods of nucleic acid amplification and sequencing
US6532978B1 (en) 1998-11-20 2003-03-18 Sepiatec Gmbh Method and device for regulating individual sub-flows of a system for conveying fluid media
US6911151B1 (en) 1998-11-20 2005-06-28 Sepiatec Gmbh Device and method for the parallel separation of substances by liquid chromatography
US20020031833A1 (en) 1998-12-22 2002-03-14 Herbert Heyneker Apparatus and method for concurrent chemical synthesis
US20040241998A1 (en) * 1999-01-22 2004-12-02 Hanson Kyle M. System for processing a workpiece
US6143252A (en) 1999-04-12 2000-11-07 The Perkin-Elmer Corporation Pipetting device with pipette tip for solid phase reactions
US6346423B1 (en) 1999-07-16 2002-02-12 Agilent Technologies, Inc. Methods and compositions for producing biopolymeric arrays
US6887715B2 (en) 1999-07-16 2005-05-03 Agilent Technologies, Inc. Methods and compositions for producing biopolymeric arrays
US8669053B2 (en) 1999-08-18 2014-03-11 Illumina, Inc. Compositions and methods for preparing oligonucleotide solutions
US9745573B2 (en) 1999-08-18 2017-08-29 Illumina, Inc. Compositions and methods for preparing oligonucleotide solutions
US9416411B2 (en) 1999-08-18 2016-08-16 Illumina, Inc. Compositions and methods for preparing oligonucleotide solutions
US7604996B1 (en) 1999-08-18 2009-10-20 Illumina, Inc. Compositions and methods for preparing oligonucleotide solutions
US6171797B1 (en) 1999-10-20 2001-01-09 Agilent Technologies Inc. Methods of making polymeric arrays
US6329210B1 (en) 1999-10-29 2001-12-11 Agilent Technologies, Inc. Method and apparatus for high volume polymer synthesis
US20090023605A1 (en) 1999-12-13 2009-01-22 Michal Lebl Oligonucleotide synthesizer
US7390459B2 (en) 1999-12-13 2008-06-24 Illumina, Inc. Oligonucleotide synthesizer
US20110143965A1 (en) 1999-12-13 2011-06-16 Michal Lebl Oligonucleotide synthesizer
US6663832B2 (en) 1999-12-13 2003-12-16 Illumina, Inc. Oligonucleotide synthesizer
US8465694B2 (en) 1999-12-13 2013-06-18 Illumina, Inc. Oligonucleotide synthesizer
US20020044894A1 (en) 1999-12-13 2002-04-18 Michal Lebl Oligonucleotide synthesizer
US20030223909A1 (en) 2000-02-03 2003-12-04 Cellular Process Chemistry, Inc. Scalable continuous production system
US7435392B2 (en) 2000-02-03 2008-10-14 Acclavis, Llc Scalable continuous production system
US7413714B1 (en) 2000-07-16 2008-08-19 Ymc Co. Ltd. Sequential reaction system
US20050244885A1 (en) 2000-07-31 2005-11-03 Wolber Paul K Array based methods for synthesizing nucleic acid mixtures
US20040132040A1 (en) 2000-11-16 2004-07-08 Hamill Brendan James Polynucleotide analysis using combinatorial pcr
US20110028340A1 (en) 2000-11-16 2011-02-03 Point-2-Point Genomics Limited Polynucleotide analysis using combinatorial pcr
US20080261220A1 (en) 2000-11-30 2008-10-23 Third Wave Technologies, Inc. Nucleic Acid Detection Assays
US20020142454A1 (en) 2001-01-26 2002-10-03 Third Wave Technologies, Inc. Nucleic acid synthesizers
US7435390B2 (en) 2001-01-26 2008-10-14 Third Wave Technologies, Inc. Nucleic acid synthesizers
US6932943B1 (en) 2001-01-26 2005-08-23 Third Wave Technologies Nucleic acid synthesizers
US20090041634A1 (en) 2001-01-26 2009-02-12 Third Wave Technologies, Inc. Nucleic Acid Synthesizers
US20020142341A1 (en) * 2001-03-28 2002-10-03 Makoto Kameyama Method and apparatus for producing probe carrier
US20040151628A1 (en) * 2001-05-03 2004-08-05 Honkanen Peter D High throughput microarray spotting system and method
US20020176811A1 (en) 2001-05-16 2002-11-28 Konan Peck Apparatus and methods for chemical synthesis
US6867050B2 (en) 2001-05-16 2005-03-15 Academia Sinica Apparatus and methods for chemical synthesis
US20030113237A1 (en) 2001-08-15 2003-06-19 Third Wave Technologies, Inc. Polymer synthesizer
US20030086829A1 (en) 2001-10-24 2003-05-08 Livesay Eric A. High throughput chemical synthesizer
US20030182068A1 (en) 2001-10-30 2003-09-25 Battersby Bronwyn J. Device and methods for directed synthesis of chemical libraries
US7411061B2 (en) 2001-10-31 2008-08-12 Agilent Technologies, Inc. Method of synthesizing polynucleotides using ionic liquids
US6846454B2 (en) 2001-12-24 2005-01-25 Agilent Technologies, Inc. Fluid exit in reaction chambers
US20080038724A9 (en) 2002-03-01 2008-02-14 Integrated Dna Technologies, Inc. Methods for amplifying polymeric nucleic acids
US7249529B2 (en) 2003-03-28 2007-07-31 Protedyne Corporation Robotically manipulable sample handling tool
US9492820B2 (en) 2003-09-19 2016-11-15 Applied Biosystems, Llc High density plate filler
US20050169816A1 (en) 2003-12-15 2005-08-04 Kirshner Brian M. Automated oligomer synthesis
US20130165349A1 (en) 2004-06-30 2013-06-27 Life Technologies Corporation Synthesis of oligomers in arrays
US20160256844A1 (en) 2004-06-30 2016-09-08 Applied Biosystems, Llc Synthesis of oligomers in arrays
US9283535B2 (en) 2004-06-30 2016-03-15 Applied Biosystems, Llc Synthesis of oligomers in arrays
US20110123411A1 (en) 2004-06-30 2011-05-26 Life Technologies Corporation Synthesis of oligomers in arrays
US20060182609A1 (en) * 2004-11-23 2006-08-17 Guerra Lawrence E Robotic arm for use with pharmaceutical unit of use transport and storage system
US8073666B2 (en) 2004-12-07 2011-12-06 Illumina, Inc. Systems and methods for ordering oligonucleotides
US7647186B2 (en) 2004-12-07 2010-01-12 Illumina, Inc. Oligonucleotide ordering system
US20070117178A1 (en) 2005-09-14 2007-05-24 Heiner David L Continuous polymer synthesizer
US20110136696A1 (en) 2005-09-14 2011-06-09 Illumina, Inc. Continuous polymer synthesizer
US7914739B2 (en) 2005-09-14 2011-03-29 Illumina, Inc. Continuous polymer synthesizer
US8731721B2 (en) 2005-09-14 2014-05-20 Illumina, Inc. Continuous polymer synthesizer
US20070110638A1 (en) 2005-09-14 2007-05-17 Heiner David L Continuous polymer synthesizer
US20070096674A1 (en) * 2005-10-28 2007-05-03 Fanuc Ltd Robot control device
US20070276965A1 (en) * 2006-05-03 2007-11-29 Data I/O Corporation Automated programming system employing smart interfaces
US20080058512A1 (en) 2006-08-31 2008-03-06 Leproust Eric M Apparatuses and methods for oligonucleotide preparation
US20080058511A1 (en) 2006-08-31 2008-03-06 John Hargreaves Methods and compositions useful in the preparation of oligonucleotides
US8415138B2 (en) 2006-08-31 2013-04-09 Agilent Technologies, Inc. Apparatuses and methods for oligonucleotide preparation
US9322063B2 (en) 2007-01-26 2016-04-26 Illumina, Inc. Efficient biomolecule recycling method and system
US9765396B2 (en) 2007-01-26 2017-09-19 Illumina, Inc. Efficient biomolecule recycling method and system
US8784745B2 (en) 2007-06-21 2014-07-22 Gen-Probe Incorporated Methods for manipulating liquid substances in multi-chambered receptacles
US20100273264A1 (en) * 2007-09-24 2010-10-28 Timothy Stout Apparatus for and method of preparing plant tissue for plant production
US20090148353A1 (en) 2007-12-07 2009-06-11 Thomas Downing Polymer Synthesizer
US8211370B2 (en) 2007-12-07 2012-07-03 Thomas Downing Polymer synthesizer
US8198028B2 (en) 2008-07-02 2012-06-12 Illumina Cambridge Limited Using populations of beads for the fabrication of arrays on surfaces
US9079148B2 (en) 2008-07-02 2015-07-14 Illumina Cambridge Limited Using populations of beads for the fabrication of arrays on surfaces
US9677069B2 (en) 2008-07-02 2017-06-13 Illumina Cambridge Limited Nucleic acid arrays of spatially discrete features on a surface
US20110172127A1 (en) 2008-08-27 2011-07-14 Westemd Asset Clearinghouse Company, LLC Methods and Devices for High Fidelity Polynucleotide Synthesis
US8808986B2 (en) 2008-08-27 2014-08-19 Gen9, Inc. Methods and devices for high fidelity polynucleotide synthesis
US9856471B2 (en) 2008-08-27 2018-01-02 Gen9, Inc. Methods and devices for high fidelity polynucleotide synthesis
US20140309119A1 (en) 2008-08-27 2014-10-16 Gen9, Inc. Methods and Devices for High Fidelity Polynucleotide Synthesis
US20100248981A1 (en) * 2009-03-27 2010-09-30 Affymetrix, Inc. System and methods for processing microarrays
US20120220497A1 (en) 2009-11-03 2012-08-30 Gen 9, Inc. Methods and Microfluidic Devices for the Manipulation of Droplets in High Fidelity Polynucleotide Assembly
US9073033B2 (en) 2010-01-19 2015-07-07 Illumina, Inc. Methods and compositions for processing chemical reactions
US9115348B2 (en) 2010-05-10 2015-08-25 The Regents Of The University Of California Endoribonuclease compositions and methods of use thereof
US20150369267A1 (en) 2010-10-08 2015-12-24 Integrated Dna Technologies, Inc. Well drain system for use with multi-well synthesizer
US8575071B2 (en) 2010-11-03 2013-11-05 Illumina, Inc. Reducing adapter dimer formation
US9506055B2 (en) 2010-11-03 2016-11-29 Illumina, Inc. Reducing adapter dimer formation
US20130296192A1 (en) 2010-11-12 2013-11-07 Gen9, Inc. Protein Arrays and Methods of Using and Making the Same
US9238671B2 (en) 2011-01-28 2016-01-19 Illumina, Inc. Oligonucleotide replacement for di-tagged and directional libraries
US20120308346A1 (en) * 2011-06-03 2012-12-06 Arthur Keigler Parallel single substrate processing system loader
US9370551B2 (en) 2011-07-27 2016-06-21 The Broad Institute, Inc. Compositions and methods of treating head and neck cancer
US9040678B2 (en) 2011-08-05 2015-05-26 Illumina, Inc. Functionalization and purification of molecules by reversible group exchange
US9598453B2 (en) 2011-08-05 2017-03-21 Illumina, Inc. Functionalization and purification of molecules by reversible group exchange
US8481309B2 (en) 2011-11-30 2013-07-09 The Broad Institute Inc. Nucleotide-specific recognition sequences for designer TAL effectors
US8450107B1 (en) 2011-11-30 2013-05-28 The Broad Institute Inc. Nucleotide-specific recognition sequences for designer TAL effectors
US8507272B2 (en) 2011-11-30 2013-08-13 The Broad Institute Inc. Nucleotide-specific recognition sequences for designer TAL effectors
US8614092B2 (en) 2011-11-30 2013-12-24 The Broad Institute Inc. Nucleotide-specific recognition sequences for designer TAL effectors
US9150896B2 (en) 2012-09-06 2015-10-06 Illumina, Inc. Nucleotides and primers with removable blocking groups
US8889356B2 (en) 2012-12-12 2014-11-18 The Broad Institute Inc. CRISPR-Cas nickase systems, methods and compositions for sequence manipulation in eukaryotes
US8895308B1 (en) 2012-12-12 2014-11-25 The Broad Institute Inc. Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation
US8993233B2 (en) 2012-12-12 2015-03-31 The Broad Institute Inc. Engineering and optimization of systems, methods and compositions for sequence manipulation with functional domains
US8871445B2 (en) 2012-12-12 2014-10-28 The Broad Institute Inc. CRISPR-Cas component systems, methods and compositions for sequence manipulation
US8865406B2 (en) 2012-12-12 2014-10-21 The Broad Institute Inc. Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation
US8945839B2 (en) 2012-12-12 2015-02-03 The Broad Institute Inc. CRISPR-Cas systems and methods for altering expression of gene products
US8795965B2 (en) 2012-12-12 2014-08-05 The Broad Institute, Inc. CRISPR-Cas component systems, methods and compositions for sequence manipulation
US8771945B1 (en) 2012-12-12 2014-07-08 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products
US8999641B2 (en) 2012-12-12 2015-04-07 The Broad Institute Inc. Engineering and optimization of systems, methods and compositions for sequence manipulation with functional domains
US8697359B1 (en) 2012-12-12 2014-04-15 The Broad Institute, Inc. CRISPR-Cas systems and methods for altering expression of gene products
US8932814B2 (en) 2012-12-12 2015-01-13 The Broad Institute Inc. CRISPR-Cas nickase systems, methods and compositions for sequence manipulation in eukaryotes
US8906616B2 (en) 2012-12-12 2014-12-09 The Broad Institute Inc. Engineering of systems, methods and optimized guide compositions for sequence manipulation
US20140357530A1 (en) 2012-12-12 2014-12-04 The Broad Institute Inc. Functional genomics using crispr-cas systems, compositions, methods, knock out libraries and applications thereof
US8889418B2 (en) 2012-12-12 2014-11-18 The Broad Institute Inc. Engineering and optimization of improved systems, methods and enzyme compositions for sequence manipulation
WO2014131833A1 (en) 2013-02-27 2014-09-04 Helmholtz Zentrum München Deutsches Forschungszentrum Für Gesundheit Und Umwelt (Gmbh) Gene editing in the oocyte by cas9 nucleases
US20140274809A1 (en) 2013-03-15 2014-09-18 Integrated Dna Technologies, Inc. Multi-well manifold assembly system for oligonucleotide synthesis
US20140273233A1 (en) 2013-03-15 2014-09-18 Sigma-Aldrich Co., Llc Crispr-based genome modification and regulation
US20150071889A1 (en) 2013-04-04 2015-03-12 President And Fellows Of Harvard College THERAPEUTIC USES OF GENOME EDITING WITH CRISPR/Cas SYSTEMS
US9069358B2 (en) 2013-06-24 2015-06-30 Biolytic Lab Performance, Inc. System for controlling and optimizing reactions in solid phase synthesis of small molecules

Non-Patent Citations (20)

* Cited by examiner, † Cited by third party
Title
Advanced Analytical®, Oligo PRO™ Automated Purity Analyzers, 2016, 4 pages.
Applied Biosystems, Applied Biosystems 3400 DNA Synthesizer, © 2007, 4 pages.
AsahiKASEI Bioprocess, Oligonucleotide Synthesizers, © 2014 Asahi Kasei Bioprocess-All rights reserved, 4 pages.
Beckman Instruments Inc., Oligo Series 1000 DNA Synthesis Systems, BR-8046A, ©1996 Beckman Instruments Inc., 12 Pages.
Deval A. Lashkari et al., "An automated multiplex oligonucleotide synthesizer: Develpment of high-throughput, low-cost DNA synthesis", Proc. Natl. Acad. Sci. USA, vol. 92, pp. 7912-7915, Aug. 1995, Applied Biological Sciences.
Dr. Oligo®, AZCO BioTech, Inc., -96/192 DNA/RNA High throughput Synthesizer, 2014, 24 pages.
General Electric Company ©2006, ÄKTA oligopilot plus, Oligonucleotide synthesis, Data File 18/1144-66 AD, Mar. 2006, 8 pages.
J. Karafilidis, "Oligonucleotide Synthesis", ACROS Organics Part of Thermo Fisher Scientific, 2008, 8 pages.
Ji-Yen Cheng et al., "High throughput parallel synthesis of oligonucleotides with 1536 channel synthesizer", Nucleic Acids Research, 2002, vol. 30 No. 18 e93, © 2002 Oxford University Press, 7 pages.
Linda E Sindelar et al., "High-throughput DNA synthesis in a multichannel format", Nucleic Acids Research, 1995, vol. 23, No. 6: 982-987, ©1995 Oxford University Press.
Marco Karsten et al., Dionex Corporation, ©2006, Increasing Throughput in LC and LC-MS with a Parallel HPLC System, PITTCON 2006 Presentation, 5 pages.
Michael Jensen et al., "Next generation 1536-well oligonucleotide synthesizer with on-the-fly dispense", Journal of Biotechnology 171 (2014) 76-81.
Richard C King et al., "Description and validation of a staggered parallel high performance liquid chromatography system for good laboratory practice level quantitative analysis by liquid chromatography/tandem mass spectrometry", Rapid Commun. Mass Spectrum. 2002; 16: 43-52, Copyright ©2001 John Wiley & Sons, Ltd.
Sepiatec GMBH, Technical Data Sepmatix 8x HPLC, © copyright 2012 Sepiatec GmbH, 4 pages.
Simon Rayner et al., "MerMade: An Oligodeoxyribonucleotide Synthesizer for High Throughput Oligonucleotide Production in Dual 96-Well Plates" GENOME RESEARCH, 8:741-747 ©1998 by Cold Spring Harbor Laboratory Press ISSN 1054-9803/98, 7 Pages.
Sriram Kosuri et al., "Large-scale de novo DNA synthesis: technologies and applications", Nature Methods, vol. 1 No. 5, May 2014, 499-507, © 2014 Nature America, Inc.
STC Analytics, HPLC PAL Systems, Front-End Automation for LC/LC-MS Systems, ©2017, 8 pages.
Teledyne Isco, A Teledyne Technologies Company, CombiFlash® Optix 10 Installation and Operation Guide, copyright © 2000, Teledyne Isco, Inc., Revision F, May 1, 2007, 82 pages.
Thermo Fisher Scientific Inc., ©2010, Multiplexing Technology Thermo Scientific Transcend LX System, Product Specifications, 2 Pages.
Waters the Science of What's Possible™, Alliance HPLC High Through System, © Oct. 2008, 7 pages.

Also Published As

Publication number Publication date
US20180311637A1 (en) 2018-11-01

Similar Documents

Publication Publication Date Title
Kang et al. Comparative glycomic mapping through quantitative permethylation and stable-isotope labeling
US5985214A (en) Systems and methods for rapidly identifying useful chemicals in liquid samples
US5609826A (en) Methods and apparatus for the generation of chemical libraries
Wollscheid et al. Mass-spectrometric identification and relative quantification of N-linked cell surface glycoproteins
EP1272856B1 (en) System and method for dispensing solution to a multi-well container
US6951575B2 (en) Method for performing high density submicroliter crystallization experiments
US5273718A (en) Apparatus for carrying out biochemical reactions
Sawada et al. Widely targeted metabolomics based on large-scale MS/MS data for elucidating metabolite accumulation patterns in plants
Tyers et al. From genomics to proteomics
EP1322413B1 (en) Method and apparatus for processing biomolecule arrays
US7429359B2 (en) Source and target management system for high throughput transfer of liquids
US6225061B1 (en) Systems and methods for performing reactions in an unsealed environment
US6296673B1 (en) Methods and apparatus for performing array microcrystallizations
US20040029260A1 (en) Automated system for isolating, amplifying and detecting a target nucleic acid sequence
US6799120B2 (en) Nonredundant split/pool synthesis of combinatorial libraries
US9236236B2 (en) System layout for an automated system for sample preparation and analysis
US6696298B2 (en) Multi-channel reagent dispensing apparatus
CN102803147B (en) General sample preparation system and the use of the integrated analysis system
CN103221529B (en) Apparatus and methods for integrated sample preparation, reaction and detection
JP4149736B2 (en) Nucleic acid sample, proteins, and hybridization chamber for making hybrids of tissue fragments, processor, and apparatus for providing a system
Petrik Microarray technology: the future of blood testing?
Bhambure et al. High-throughput process development for biopharmaceutical drug substances
US9101921B2 (en) Carrier enclosing tip, carrier treating apparatus and method of carrier treatment
JP4080547B2 (en) Analysis of molecular
Lewis et al. Controlling misdiagnosis errors in preimplantation genetic diagnosis: a comprehensive model encompassing extrinsic and intrinsic sources of error